This invention relates to amino-tetralin derivatives, associated acceptable salts, or hydrates thereof, and associated compositions and methods for use as M2/M3 selective muscarinic receptor antagonists.
Acetylcholine (Ach) is the principal transmitter of the parasympathetic nervous system. The physiological actions of Ach are mediated by activation of either nicotinic or muscarinic receptors. Both of these receptor classes are heterogeneous: e.g., the muscarinic receptor family comprises five subtypes (M1, M2, M3, M4, and M5) each encoded by distinct genes and possessing unique pharmacology and distribution.
Almost all smooth muscle tissues express both muscarinic M2 and M3 receptors, both of which have a functional role. M2 receptors outnumber M3 receptors by a proportion of approximately 4 to 1. Generally, M3 receptors mediate the direct contractile effects of acetylcholine in the vast majority of smooth muscle tissues. M2 receptors, on the other hand, cause smooth muscle contraction indirectly by inhibiting sympathetically (xcex2-adrenoreceptor)-mediated relaxation.
Compounds that act as antagonists of muscarinic receptors have been used to treat several disease states associated with improper smooth muscle function, as well as in the treatment of cognitive and neurodegenerative disorders such as Alzheimer""s disease. Until recently, most of these compounds have been non-selective for the various muscarinic receptor subtypes, leading to unpleasant anti-cholinergic side-effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side-effects is dry-mouth resulting from muscarinic receptor blockade in the salivary gland. Recently developed M2 or M3 specific antagonists have been shown to have reduced side effects. Evidence suggests that mechanistically, concurrent blockade of M2 and M3 receptors could be therapeutically effective in the treatment of disease states associated with smooth muscle disorders.
Additionally, muscarinic receptor antagonists are front-line therapy as bronchodilators in chronic obstructive pulmonary disease (COPD). It is thought that the efficacy of this class of molecules is mediated through antagonism of the natural transmitter (acetyocholine) at M3 receptors on airway smooth muscle and there may be additional benefit in COPD through inhibition of mucus secretion which may also be mediated through M3 receptors. The current standard antimuscarinic for the treatment of COPD is ipratropium (Atrovent) which is administered by aerosol 4 times per day. More recently tiotropium (Spiriva) has been developed by Boehringer-Ingelheim as a second-generation muscarinic antagonist and is expected to be launched in 2002 (in collaboration with Pfizer). Tiotropium is also given by aerosol but has a slow off-rate from the M3 receptor and, as a result, causes a prolonged bronchodilatation. Tiotropium will be given once per day. Although tiotropium has high affinity for all muscarinic receptor subtypes, it is a quaternary ammonium compound which is poorly absorbed.
Few M2/M3 selective antagonists have been developed. The present invention fills this need by providing these types of antagonists useful in the treatment of disease states associated with improper smooth muscle function and respiratory disorders.
This invention relates to compounds comprising Formula I: 
wherein:
R1 is (C1-6)alkyl;
R2 is halogen or xe2x80x94ORxe2x80x2;
R3 is hydrogen or xe2x80x94ORxe2x80x2;
Rxe2x80x2 is hydrogen, (C1-6)alkyl, or SO2Rxe2x80x3;
Rxe2x80x3 is (C1-6)alkyl, haloalkyl,
aryl or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with a group selected from (C1-6)alkyl, halo, haloalkyl, cyano, nitro, alkylsulfonyl, and alkylsulfonylamino,
R4 is (C1-6)alkyl,
aryl, heterocyclyl, or heteroaryl, wherein said aryl, heterocyclyl or heteroaryl groups are optionally substituted with a group selected from (C1-6)alkyl, halo, haloalkyl, (C1-6)alkoxy, cyano, amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl, urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl, alkoxycarbonyl, heterocyclyl and heteroaryl,
or xe2x80x94NR5R6; and
R5 and R6 are independently of each other hydrogen, (C1-6)alkyl,
aryl or heterocyclyl; wherein said aryl or heterocyclyl groups are optionally substituted with (C1-6)alkyl, halo, haloalkyl, cyano, (C1-6)alkoxy, and alkylsulfonyl,
or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or salts or solvates thereof.
In preferred embodiments R2 is (C1-6)alkoxy, hydroxy or xe2x80x94OSO2Rxe2x80x3 wherein Rxe2x80x3 is (C1-6)alkyl, haloalkyl, aryl or heteroaryl, and R3 is hydrogen or (C1-6)alkyl; in another preferred embodiment R2 is (C1-6)alkoxy and R3 is hydrogen, and in another preferred embodiment R2 and R3 are (C1-6)alkoxy.
In another preferred embodiment R4 is (C1-6)alkyl, and within this embodiment other preferred group of compounds is that wherein R1 is ethyl or propyl.
In another preferred embodiment R4 is an aryl group; and in another preferred embodiment R4 is phenyl optionally substituted with a group selected from (C1-6)alkyl, halo, haloalkyl, (C1-6)alkoxy, cyano, amino, mono- or di alkylamino, nitro, alkylsulfonyl, alkylcarbonyl, urea, alkylcarbonylamino, alkylsulfonylamino, alkylaminosulfonyl, alkoxycarbonyl, heterocyclyl and heteroaryl, and within this embodiment other preferred group of compounds is that wherein R1 is ethyl or propyl. Another preferred group of compounds is that wherein R2 is xe2x80x94ORxe2x80x2, and R3 is xe2x80x94ORxe2x80x2 or hydrogen.
In another preferred embodiment R4 is a heteroaryl group; and in another preferred embodiment R4 is selected from furanyl, thiophenyl, isooxazolyl, oxazolyl, imidazolyl, and pyrazolyl, all optionally substituted with one or two (C1-6) alkyl, and within this embodiment another preferred group of compounds is that wherein R1 is ethyl or propyl, and another preferred group of compounds is that wherein R2 is xe2x80x94ORxe2x80x2, and R3 is xe2x80x94ORxe2x80x2 or hydrogen.
In another preferred embodiment R4 is a heterocyclyl group; and in another preferred embodiment R4 is piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepanyl, all optionally substituted with one or two (C1-6)alkyl or alkylcarbonyl groups, and within this embodiment another preferred group of compounds is that wherein R1 is ethyl or propyl, and another preferred group of compounds is that wherein R2 is xe2x80x94ORxe2x80x2, and R3 is xe2x80x94ORxe2x80x2 or hydrogen.
In another preferred embodiment R4 is xe2x80x94NR5R6, and R5 is (C1-6)alkyl and R6 is hydrogen or (C1-6)alkyl; and in another preferred embodiment R4 is xe2x80x94NR5R6, R5 is heterocyclyl and R6 is hydrogen, and within this embodiment another preferred group of compounds is that wherein R1 is ethyl or propyl, and another preferred group of compounds is that wherein R2 is xe2x80x94ORxe2x80x2, and R3 is xe2x80x94ORxe2x80x2 or hydrogen.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers and salts or solvates thereof, in admixture with at least one suitable carrier.
In another aspect, this invention relates to a method of treatment of a disease in a mammal treatable by administration of at least one compound of Formula I, having selective activity for the M2 and M3 muscarinic receptors, in particular a method of treatment in a subject having a disease state comprising smooth muscle disorders; preferably genitourinary tract disorders, respiratory tract disorders, gastrointestinal tract disorders; more preferably genitourinary tract disorders such as overactive bladder or detrusor hyperactivity and its symptoms, such as the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficiency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like. In another preferred embodiment, the disease comprises respiratory tract disorders such as allergies and asthma. In another preferred embodiment, the disease state comprises gastrointestinal disorders.
In another aspect, the invention relates to a process for preparing a compound of Formula I, which process comprises reacting a compound having a general formula d: 
wherein R1, R2, and R3 are as described in the summary of the invention, with a compound of formula R4C(O)L, wherein L is a leaving group and R4 is as described in the summary of the invention, to give a compound of Formula I: 
wherein R1, R2, R3 and R4 are as described in the summary of the invention.